title: Tamoxifen inhibition of kv7.2/kv7.3 channels.
abstract: KCNQ genes encode five Kv7 K(+) channel subunits (Kv7.1-Kv7.5). Four of these (Kv7.2-Kv7.5) are expressed in the nervous system. Kv7.2 and Kv7.3 are the principal molecular components of the slow voltage-gated M-channel, which regulates neuronal excitability. In this study, we demonstrate that tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibits Kv7.2/Kv7.3 currents heterologously expressed in human embryonic kidney HEK-293 cells. Current inhibition by tamoxifen was voltage independent but concentration-dependent. The IC50 for current inhibition was 1.68 ± 0.44 µM. The voltage-dependent activation of the channel was not modified. Tamoxifen inhibited Kv7.2 homomeric channels with a higher potency (IC50 = 0.74 ± 0.16 µM). The mutation Kv7.2 R463E increases phosphatidylinositol- 4,5-bisphosphate (PIP2) - channel interaction and diminished dramatically the inhibitory effect of tamoxifen compared with that for wild type Kv7.2. Conversely, the mutation Kv7.2 R463Q, which decreases PIP2 -channel interaction, increased tamoxifen potency. Similar results were obtained on the heteromeric Kv7.2 R463Q/Kv7.3 and Kv7.2 R463E/Kv7.3 channels, compared to Kv7.2/Kv7.3 WT. Overexpression of type 2A PI(4)P5-kinase (PIP5K 2A) significantly reduced tamoxifen inhibition of Kv7.2/Kv7.3 and Kv7.2 R463Q channels. Our results suggest that tamoxifen inhibited Kv7.2/Kv7.3 channels by interfering with PIP2-channel interaction because of its documented interaction with PIP2 and the similar effect of tamoxifen on various PIP2 sensitive channels.
authors.affiliation: Unidad de Investigación "Carlos Méndez" del Centro Universitario de Investigaciones Biomédicas de la Universidad de Colima, Colima, Col. México.
authors.forename: Tania
authors.initials: T
authors.lastname: Ferrer
authors.forename: Ivan Arael
authors.initials: IA
authors.lastname: Aréchiga-Figueroa
authors.forename: Mark S
authors.initials: MS
authors.lastname: Shapiro
authors.forename: Martin
authors.initials: M
authors.lastname: Tristani-Firouzi
authors.forename: José A
authors.initials: JA
authors.lastname: Sanchez-Chapula
mesh_terms: D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D051658:KCNQ2 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051659:KCNQ3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology*
chemical_list: D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D013629:Tamoxifen; C514871:PIP4K2A protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor)